Posted on Dec 08, 2020, 5 p.m.
According to a study published in the journal eLife, researchers from the University of California San Francisco have shown rapid restoration of youthful cognitive abilities in aged mice which was accompanied by rejuvenation of brain and immune cells that could help to explain the improvements in brain function.
The report describes how a few doses of the experimental drug called ISRIB reversed age-related declines in memory and mental flexibility in aged mice. ISRIB has already been shown in lab studies to restore memory function months after traumatic brain injury, reverse cognitive impairments in Down Syndrome, prevent noise-related hearing loss, fight certain types of prostate cancer, and enhance cognition in healthy animals.
“ISRIB’s extremely rapid effects show for the first time that a significant component of age-related cognitive losses may be caused by a kind of reversible physiological blockage rather than more permanent degradation,” explained Susanna Rosi, Ph.D., Lewis and Ruth Cozen Chair II and professor of Neurological Surgery, Physical Therapy, and Rehabilitation Science.
“The data suggests that the aged brain has not permanently lost essential cognitive capacities, as was commonly assumed, but rather that these cognitive resources are still there but have been somehow blocked, trapped by a vicious cycle of cellular stress. Our work with ISRIB demonstrated a way to break that cycle and restore cognitive abilities that had become walled off over time” adds Peter Walter, Ph.D., and professor of the Department of Biochemistry and Biophysics as well as a Howard Hughes Medical Institute Investigator.
The question remains if rebooting the cellular protein production will hold the key to aging and other diseases in humans. ISRIB was discovered in 2013 to work by rebooting cells’ protein production machinery after it is throttled by one of three stress responses; ISRIB stands for ISR inhiBitor.
ISR normally detects problems with protein production within a cell and responds by halting the cell’s protein synthesis machinery, and this safety mechanism is crucial to finding dysfunctioning cells, but if stuck in the on position in a tissue such as the brain can lead to serious problems as cells lose the ability to perform their normal activities. Recent animal studies have implicated chronic ISR activation in the persistent cognitive and behavioral deficits seen in patients after TBI, by showing that brief ISRIB treatment can reboot the ISR and restore normal brain function almost overnight, at least in mice.
“We’ve seen how ISRIB restores cognition in animals with traumatic brain injury which in many ways is like a sped-up version of age-related decline,” says Rosi, who is also the director of neurocognitive research. “It may seem like a crazy idea, but asking whether the drug could reverse symptoms of ageing itself was just a logical next step.”
For this study aged mice were trained to escape from a watery maze by finding a hidden platform, this task is typically hard for older animals to learn. Older animals receiving small doses of ISRIB daily during the 3-day process were able to accomplish the task as well as youthful mice, and much better than the untreated control animals of the same age.
To test how long the cognitive rejuvenation lasted and whether it could generalize to other cognitive skills several weeks after the initial ISRIB treatment the same mice were trained to find their way out of a maze with an exit that changed daily. This is a test of mental flexibility for aged mice who tend to get increasingly stuck in their ways. The previously treated older animals still performed at youthful levels while the untreated control animals continued to struggle.
The researchers studied the activity and anatomy of cells in the hippocampus of the animals to understand how ISRIB might be improving brain function one day after receiving a single dose of the experimental drug. The researchers found that overnight common signatures of neuronal aging had disappeared: neuron electrical activity became more sprightly and responsive to stimulation, and cells showed more robust connectivity with cells around them while also showing an ability to form stable connections with one another at levels usually only seen in younger mice.
ISRIB was also discovered to alter the function of the immune system T-cells which are prone to age-related dysfunction; findings suggest another path by which the experimental drug may be improving cognition in the treated age animals, and this may have implication for diseases ranging from diabetes to Alzheimer’s disease that are linked to heightened inflammation that is caused by an aging immune system.
“This was very exciting to me because we know that aging has a profound and persistent effect on T cells and that these changes can affect brain function in the hippocampus. At the moment, this is just an interesting observation, but it gives us a very exciting set of biological puzzles to solve,” said Rosi.
Thus far the researchers have not observed any serious side effects when interfering with the ISR cellular safety mechanism. Walter says this may be due to two factors: taking only a few doses to reset unhealthy chronic ISR activation back to a healthier state, and ISRIB having virtually no effect when applied to cells actively employing ISR in its most powerful form, such as in against an aggressive viral infection. Both factors make the molecule much less likely to have negative side effects making it more attractive as a potential therapeutic.
“It almost seems too good to be true,” says Walter, “but with ISRIB we seem to have hit a sweet spot for manipulating the ISR with an ideal therapeutic window.”
Chronic ISR activation and the resulting blockage of cellular protein production as it turns out may play a role in a wide array of neurological conditions which based on this study could potentially be treated with an ISR resetting agent like the experimental drug ISRIB such as Prion Disease, Vanishing White Matter Disorder, Down Syndrome, Multiple Sclerosis, Parkinson’s Disease, Alzheimer’s Disease, Traumatic Brain Injury, Frontotemporal Dementia, Amyotrophic Lateral Sclerosis, and Age-Related Cognitive Decline, according to a recent review by Walter and colleague Mauro Costa-Mattioli of the Baylor College of Medicine.
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